Tumors are new creatures formed in the body due to actions of a variety of oncogenic factors and the following changes of genetic material of cells resulting in abnormal gene expression and cell proliferation. The tumor cells lose their normal growth regulatory function and have autonomous or relatively autonomous growth ability. The tumor cells can continue to grow even the oncogenic factors disappear and will cause a consumption of large quantities of human's nutrients. If not being found and treated early, the cancer cells will be transferred and grow throughout the body, and release a variety of toxins that cause the body weight loss, anemia, organ failure and even death.
The method of treating tumors mainly includes three aspects: drug therapy, surgery and radiation therapy. Drug therapy is becoming increasingly important in cancer treatment since surgery and radiation therapy are difficult to eradicate the tumor and fail to show obvious effect in patients with the mid-advanced cancer. Conventional anticancer drugs do not distinguish between tumor cells and normal cells, and often cause serious side effects. Targeted drugs specifically target to cancer cells and can accurately act on the tumor, which greatly improves the level of treatment and reduces the adverse response rate, such as making the median survival time of patients with advanced colorectal cancer increased 66.7%, and the efficiency of the treatment of advanced breast cancer increased 71.3%.
As pharmaceutical companies are accelerating the development of targeted antineoplastic drugs, and there is a great market demand for this class of antineoplastic drugs, molecular targeted drugs have become the world's fastest growing unit in the worldwide market.
Phosphatidylinositol 3-kinase (PI3K) pathway is the most common place where human cancer cells mutate, and it can lead to cell proliferation, activation and signal amplification. PI3K and mammalian target of rapamycin (mTOR) are important kinases of PI3K signaling pathway.
PI3K is a member of lipid kinase family, it regulates cell metabolism and growth through phosphorylation at 3-position of phosphatidylinositol to produce phosphatidylinositol-triphosphate (PIP3). This PIP3, which is the second messenger of lipid, can make P13K paired with downstream effectors (especially Akt), resulting in membrane recruitment and phosphorylation, cell proliferation and activation. Therefore, inhibition of phosphatidylinositol 3-kinase can affect the PI3K pathway, thereby inhibiting cancer cell proliferation and activation.
mTOR is a serine/threonine protein kinase present in the cytoplasm, it belongs to the phosphoinositide 3-kinase-related protein kinase family and exists in organism as two complexes forms, namely mTORC1 (rapamycin target) and mTORC2 (not inhibited by rapamycin). mTOR is a cellular signal transduction protein, which regulates the response of tumor cells to nutrients and growth factors, and controls tumor blood supply through the role of vascular endothelial growth factor. mTOR inhibitors can make cancer cells starved, and reduce the tumor volume by inhibiting mTOR.
In Novartis' patent application of WO2006122806 and Pfizer's patent application of WO201003816, a series of compounds inhibiting both PI3K and mTOR have been reported. These compounds have good activity in tumor therapy. However, there is no compound inhibiting both PI3K and mTOR on the current drug market. Therefore, it is needed to develop multi-targeted drugs that have inhibiting activity for both PI3K and mTOR in order to facilitate the treatment of cancer.